Fulvestrant formulations

ABSTRACT

The invention provides a fulvestrant composition comprising a pharmaceutically acceptable vehicle and not more than 2% total impurities and which, optionally, is free of a non-aqueous ester solvent. The composition may be used to treat hormone receptor positive metastatic breast cancer in a subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of co-pending U.S. patentapplication Ser. No. 16/254,695, filed on Jan. 23, 2019, which is acontinuation of U.S. patent application Ser. No. 15/799,281, filed onOct. 31, 2017, now U.S. Pat. No. 10,188,663, which is a continuation ofU.S. patent application Ser. No. 14/996,489, filed on Jan. 15, 2016,which issued as U.S. Pat. No. 9,833,459, which is a continuation of U.S.patent application Ser. No. 14/181,244, filed on Feb. 14, 2014, now U.S.Pat. No. 9,271,990, the disclosures of which are incorporated herein byreference in their entireties for all purposes.

BACKGROUND OF THE INVENTION

Fulvestrant is an estrogen receptor antagonist, which was approved inthe United States in 2002 under the tradename FASLODEX™ for thetreatment of hormone receptor positive metastatic breast cancer inpostmenopausal women with disease progression following antiestrogentherapy. The FASLODEX™ (fulvestrant) product is approved foradministration by intramuscular injection on days 1, 15, 29, and oncemonthly thereafter. Current guidelines recommend that a volume of nomore than 5 mL is administered in a single intramuscular injection.However, fulvestrant is a highly lipophilic molecule which ispractically insoluble in water. Therefore, a formulation which containsenough fulvestrant to provide therapeutic efficacy over a period ofseveral days or weeks in a volume of 5 mL or less is desirable.

U.S. Pat. Nos. 6,774,122; 7,456,160; 8,329,680; and 8,466,139 disclosethat the introduction of a non-aqueous ester solvent which is misciblein castor oil and an alcohol surprisingly eases the solubilization offulvestrant into a concentration of at least 50 mg/mL. These patentsdisclose benzyl benzoate, ethyl oleate, isopropyl myristate, andisopropyl palmitate as preferred non-aqueous ester solvents, mostpreferably benzyl benzoate at a concentration of 15% w/v. Theformulations disclosed in U.S. Pat. Nos. 6,774,122; 7,456,160;8,329,680; and 8,466,139 encompass the FASLODEX™ (fulvestrant) product,which comprises 250 mg fulvestrant in a 5 mL solution containing 10% w/valcohol, 10% w/v benzyl alcohol, and 15% w/v benzyl benzoate ascosolvents which is made up to 100% w/v with castor oil as a cosolventand a release rate modifier (FASLODEX™ Prescribing Information, Rev.11/12). The Prescribing Information for FASLODEX™ (fulvestrant)injection indicates that the product should be stored underrefrigeration at 2°-8° C. until time of use.

Other formulations of fulvestrant have been described. U.S. Pat. No.5,183,814 discloses a formulation comprising 50 mg fulvestrant and 400mg benzyl alcohol, which is made up to 1 mL with castor oil. U.S. PatentApplication Publication 2004/0175402 discloses a formulation adapted foradministration by injection containing fulvestrant in a ricinoleatevehicle comprising an antioxidant, such as thiourea, to suppress theformation of fulvestrant oxidative degradation products and improveformulation stability. International Patent Application Publication WO2003/006064 discloses a formulation containing fulvestrant in aricinoleate vehicle comprising at least one alcohol and a non-aqueousester solvent, wherein the concentration of fulvestrant is at least 100mg/mL to facilitate less frequent dosing intervals or the administrationof a higher drug dose.

U.S. Patent Application Publication 2009/0227549 discloses a formulationsuitable for intramuscular administration comprising at least 40 mg/mLfulvestrant in a vehicle, wherein the formulation is substantially freeof castor oil and castor oil derivatives. U.S. Patent ApplicationPublication 2013/0267489 discloses a composition comprising fulvestrant;a solvent selected from dimethyl sulfoxide (DMSO), glycofurol, N-methylpyrrolidone, and mixtures thereof; an oil mixture selected from amixture of caprylic and capric triglycerides, a mixture of caprylic,capric and linoleic triglycerides, a mixture of caprylic, capric andsuccinic triglycerides, and a mixture of propylene glycol dicaprylateand propylene glycol dicaprate; and a sustained release member selectedfrom benzyl benzoate, dihydrolipoic acid, benzyl alcohol and lipoicacid, which has less than about 5% total impurities after at least about24 months of storage at about 5°-25° C.

There remains a need for formulations comprising a therapeuticallyeffective amount of fulvestrant in a pharmaceutically acceptable vehiclesuitable for intramuscular injection which are storage stable,preferably for long durations at room temperature.

BRIEF SUMMARY OF THE INVENTION

An embodiment of the invention provides a composition which containsfulvestrant, a pharmaceutically acceptable alcohol, polysorbate 80, anantioxidant, and castor oil.

Another embodiment of the invention provides a method of stabilizing afulvestrant composition, by forming a mixture comprising fulvestrant, apharmaceutically acceptable alcohol, polysorbate 80, an antioxidant, andcastor oil.

In yet another embodiment, the composition of the invention isformulated for parenteral administration and may be presented in acontainer selected from the group consisting of a vial, a bottle, acartridge, and a syringe.

The composition according to the invention is storage stable andsuitable for administration to a subject to treat or prevent a diseaseor condition, such as breast cancer.

Other embodiments, characteristics, and advantages of the invention willbe more apparent after reading the description and the examples thatfollow.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

The FIGURE depicts the time course of fulvestrant plasma concentrationupon administration to rabbits of a reference castor oil-basedformulation representing the FASLODEX™ (fulvestrant) injection product(“RLD”), or one of four castor oil-based formulations according to theinvention comprising 10% w/v benzyl alcohol, 0.12% w/v polysorbate 80,0.06% w/v α-tocopherol, 10% w/v ethanol, and 7.5% w/v fulvestrant (“A”),10% w/v benzyl alcohol, 0.12% w/v polysorbate 80, 0.06% w/vα-tocopherol, 15% w/v ethanol, and 10% w/v fulvestrant (“B”), 10% w/vbenzyl alcohol, 0.12% w/v polysorbate 80, 0.06% w/v α-tocopherol, 10%w/v ethanol, and 5% w/v fulvestrant (“C”), or 10% w/v benzyl alcohol,0.12% w/v polysorbate 80, 0.06% w/v α-tocopherol, 17% w/v ethanol, and5% w/v fulvestrant (“D”). Each data point represents the mean plasmafulvestrant concentration (n=6 rabbits per group).

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a composition which contains fulvestrant, apharmaceutically acceptable alcohol, polysorbate 80, an antioxidant, andcastor oil.

Fulvestrant(7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]oestra-1,3,5(10)-triene3,17 β-diol) has the following structural formula (1):

Fulvestrant contains six asymmetric carbon atoms and a stereogenicsulfoxide in the side chain. The active ingredient in the FASLODEX™(fulvestrant) injection product is a mixture of 2 diastereoisomers,which are referred to in the art as fulvestrant sulfoxide A and B.Fulvestrant sulfoxide A and B have the same absolute configuration ateach of the stereogenic centers in the steroid system, but differentabsolute configurations at the sulfur atom.

In any of the embodiments of the invention, the fulvestrant can befulvestrant sulfoxide A, fulvestrant sulfoxide B, or a mixture offulvestrant sulfoxide A and fulvestrant sulfoxide B. In addition, thefulvestrant can be in free form, or the fulvestrant can be in salt orsolvate form, such as a pharmaceutically acceptable fulvestrant salt orfulvestrant solvate. Thus, all salt and non-salt forms of fulvestrantand solvates of the foregoing are embraced by the invention anddescriptions of fulvestrant provided herein. The fulvestrant can becrystalline or amorphous. If crystalline, the fulvestrant can be anypolymorphic form.

In some embodiments, the amount of fulvestrant present in thecomposition is 3% w/v (weight per volume of the composition) or more,e.g., 4% w/v or more, 5% w/v or more, 5.5% w/v or more, 6% w/v or more,6.5% w/v or more, 7% w/v or more, 7.5% w/v or more, or 8% w/v or more.In other embodiments, the amount of fulvestrant present in thecomposition is 10% w/v or less, e.g., 9.5% w/v or less, 9% w/v or less,8.5% w/v or less, 8% w/v or less, 7.5% w/v or less, 7% w/v or less, 6%w/v or less, or 5.5% w/v or less. In yet other embodiments, the amountof fulvestrant present in a composition is in a range bounded by any ofthe foregoing values. For example, the amount of fulvestrant present ina composition can be 3%-10% w/v, 4%-9% w/v, 4.5%-7.5% w/v, 5%-7.5% w/v,5%-10% w/v, 6%-8% w/v, 7.5%-9.5% w/v, or 7%-10% w/v. In certainembodiments, the amount of fulvestrant present in a composition is about5% w/v, or 50 mg/mL.

The pharmaceutically acceptable alcohol can be one alcohol or a mixtureof two or more alcohols. In certain embodiments, the pharmaceuticallyacceptable alcohol is a mixture of two alcohols. Suitablepharmaceutically acceptable alcohols include, without limitation,ethanol, benzyl alcohol, or a mixture of both ethanol and benzylalcohol.

In some embodiments, the amount of pharmaceutically acceptable alcoholpresent in the composition is 3% w/v or more, e.g., 5% w/v or more, 8%w/v or more, 10% w/v or more, 12.5% w/v or more, 15% w/v or more, 16.5%w/v or more, 17.5% w/v or more, or 19% w/v or more. In otherembodiments, the amount of pharmaceutically acceptable alcohol presentin the composition is 40% w/v or less, e.g., 35% w/v or less, 32.5% w/vor less, 27% w/v or less, 22.5% w/v or less, 21% w/v or less, 20% w/v orless, 18.5% w/v or less, or 17% w/v or less. In yet other embodiments,the amount of pharmaceutically acceptable alcohol present in acomposition is in a range bounded by any of the foregoing values. Forexample, the amount of pharmaceutically acceptable alcohol present in acomposition can be 3%-35% w/v, 8%-27% w/v, 10%-27% w/v, 15%-22.5% w/v,17.5%-22.5% w/v, 19%-21% w/v, or 12.5%-17.5% w/v.

In certain embodiments, the composition comprises about 17% w/v ethanoland about 10% w/v benzyl alcohol. In some embodiments, the compositioncomprises a mixture of ethanol and benzyl alcohol present inapproximately equivalent w/v amounts, for example, about 10% w/v ethanoland about 10% w/v benzyl alcohol.

It has been surprisingly found that the inclusion of polysorbate 80 in acastor oil-based composition facilitates the solubilization offulvestrant into the composition at a concentration of 50 mg/mL orgreater without the need for a non-aqueous ester solvent.Advantageously, upon administration to a subject, the composition of theinvention provides pharmacokinetics which are similar to thepharmacokinetics provided by the FASLODEX™ (fulvestrant) injectionproduct which contains, inter alia, 15% w/v benzyl benzoate.

Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) is a viscous,water soluble yellow liquid that functions in pharmaceuticalformulations as a dispersing agent, an emollient, an emulsifying agent,a nonionic surfactant, a plasticizing agent, a solubilizing agent, astabilizing agent, and/or a suspending agent. Polysorbate 80 iscommercially available under the tradenames TWEEN™ 80, ALKEST™ TW 80,and CANARCEL™ TW 80.

In some embodiments, the amount of polysorbate 80 present in thecomposition is 0.005% w/v or more, e.g., 0.01% w/v or more, 0.05% w/v ormore, 0.08% w/v or more, 0.10% w/v or more, 0.15% w/v or more, 0.2% w/vor more, 0.25% w/v or more, or 0.3% w/v or more. In other embodiments,the amount of polysorbate 80 present in the composition is 1.0% w/v orless, e.g., 0.75% w/v or less, 0.5% w/v or less, 0.25% w/v or less, 0.2%w/v or less, 0.16% w/v or less, 0.14% w/v or less, 0.09% w/v or less, or0.07% w/v or less. In yet other embodiments, the amount of polysorbate80 present in a composition is in a range bounded by any of theforegoing values. For example, the amount of polysorbate 80 present in acomposition can be 0.005%-1.0% w/v, 0.01%-0.5% w/v, 0.05%-0.2% w/v,0.08%-0.16% w/v, 0.10%-0.14% w/v, 0.15%-0.25% w/v, or 0.2%-0.5% w/v. Incertain embodiments, the amount of polysorbate 80 present in acomposition is about 0.12% w/v.

In certain embodiments of the invention, the antioxidant is apharmaceutically acceptable antioxidant. The antioxidant can be oneantioxidant or a mixture of two or more antioxidants. One of ordinaryskill in the art will understand that the amount of antioxidantnecessary to suppress the formation of oxidative degradation products ina composition of the invention will vary based upon the selectedantioxidant and can be determined empirically through routineexperimentation. Suitable antioxidants and general concentration rangesare described, for example, in “Remington: The Science and Practice ofPharmacy,” 21^(st) edition, ed. P. Beringer, Lippincott Williams &Wilkins (2005) and in “Handbook of Pharmaceutical Excipients,” 7^(th)edition, ed. R. Rowe, Pharmaceutical Press (2012).

In some embodiments, the antioxidant is a vitamin E compound, includingone or more of α-, β-, γ-, or δ-tocopherol, and/or α-, β-, γ-, orδ-tocotrienol. The tocopherol or tocotrienol can be a d-tocopherol ord-tocotrienol (2R configuration), an l-tocopherol or l-tocotrienol (2Sconfiguration), or a mixture of a d,l-tocopherol and/or d,l-tocotrienol.

In certain embodiments, the antioxidant is α-tocopherol. In someembodiments, the amount of α-tocopherol present in the composition is0.001% w/v or more, e.g., 0.005% w/v or more, 0.01% w/v or more, 0.04%w/v or more, 0.08% w/v or more, 0.12% w/v or more, 0.18% w/v or more,0.2% w/v or more, or 0.4% w/v or more. In other embodiments, the amountof α-tocopherol present in the composition is 12% w/v or less, e.g., 8%w/v or less, 4% w/v or less, 2% w/v or less, 1% w/v or less, 0.8% w/v orless, 0.5% w/v or less, 0.1% w/v or less, or 0.08% w/v or less. In yetother embodiments, the amount of α-tocopherol present in a compositionis in a range bounded by any of the foregoing values. For example, theamount of α-tocopherol present in a composition can be 0.005%-2.0% w/v,0.01%-1% w/v, 0.01%-0.5% w/v, 0.04%-0.1% w/v, 0.04%-0.08% w/v,0.12%-0.8% w/v, or 0.2%-0.5% w/v. In certain embodiments, the amount ofα-tocopherol present in a composition is about 0.06% w/v.

The vehicle for the composition which contains fulvestrant, apharmaceutically acceptable alcohol, polysorbate 80, and an antioxidantin an oleaginous vehicle. Preferably, the oleaginous vehicle is aricinoleate vehicle, such as castor oil. In certain embodiments, thecastor oil is a super refined castor oil characterized by reducedcarbonyl value, reduced peroxide value, reduced iodine value, and/orincreased clarity as compared to USP grade castor oil. For example, insome embodiments, the castor oil used in a composition of the inventionhas a carbonyl value of 0.5 micromole/gram or less, a peroxide value of5.0 meq O₂/kg or less, an iodine value of 85 g iodine/100 g castor oilor less, and/or a Gardner 1933 value of 1.5 or less.

Methods to determine carbonyl value, peroxide value, iodine value, andclarity of a sample of castor oil are known to those of skill in theart. For example, carbonyl values can be determined by incubating asample of castor oil with excess 2,4-dinitrophenylhydrazine and atrichloroacetic acid catalyst in toluene for 30 minutes at 60° C.,quenching with ethanolic KOH, and measuring absorbance of2,4-dinitrophenylhydrazine derivatives at 430 nm and 460 nm by UV-VISspectroscopy. Peroxide and iodine values can be determined using thecurrent USP method 401 in conjunction with comparative titration.Clarity can be measured by comparing the color of a sample of castor oilto standards having known Gardner color numbers.

In some embodiments, the amount of castor oil present in the compositionis 30% w/v or more, e.g., 40% w/v or more, 50% w/v or more, 60% w/v ormore, 65% w/v or more, 70% w/v or more, 75% w/v or more, or 80% w/v ormore. In other embodiments, the amount of castor oil present in thecomposition is 90% w/v or less, e.g., 85% w/v or less, 82% w/v or less,77% w/v or less, 72% w/v or less, 67% w/v or less, 62% w/v or less, or58% w/v or less. In yet other embodiments, the amount of castor oilpresent in a composition is in a range bounded by any of the foregoingvalues. For example, the amount of castor oil present in a compositioncan be 40%-85% w/v, 50%-77% w/v, 60%-82% w/v, 70%-85% w/v, 60%-77% w/v,65%-72% w/v, or 75%-82% w/v.

In certain embodiments of the invention, the composition issubstantially free of a non-aqueous ester solvent. As used herein, whenreferencing the amount of a component in a composition (or formulation,mixture, etc.) the term “substantially free” means not more than about1.0%, e.g., not more than about 0.5%, not more than about 0.25%, notmore than about 0.1%, not more than about 0.05%, not more than about0.025%, or not more than about 0.01% of the component with reference tothe complete composition as measured using standard analyticaltechniques.

In certain embodiments of the invention, the composition is completelyfree of a non-aqueous ester solvent, i.e., the composition contains nodetectable amount of non-aqueous ester solvent as measured usingstandard analytical techniques.

The composition that includes fulvestrant, a pharmaceutically acceptablealcohol, polysorbate 80, an antioxidant, and castor oil may furtherinclude one or more other substances. Non-limiting examples of othersubstances include diluents, salts, buffers, stabilizers, solubilizers,preservatives, and tonicity modifiers.

A composition comprising fulvestrant, a pharmaceutically acceptablealcohol, polysorbate 80, an antioxidant, and castor oil can be preparedby any suitable method. In some embodiments, the composition is formedby combining the components together in a suitable vessel. Thecomponents can be combined in any order. In some embodiments, thepharmaceutically acceptable alcohol is added to a suitable vessel, thefulvestrant is added, and the mixture is stirred until the fulvestrantis dissolved. Subsequently, the polysorbate 80 and α-tocopherol areadded to the vessel, and the mixture is stirred. Next, the castor oil isadded to the vessel until the final volume is obtained, and the mixtureis stirred. In other embodiments, the pharmaceutically acceptablealcohol, polysorbate 80, and α-tocopherol are combined in a suitablevessel prior to the addition of the fulvestrant. In certain embodiments,the vessel is pressurized with nitrogen upon the addition of the castoroil.

In some embodiments, the composition is filtered through one or morefilters prior to filling the composition into one or more suitablecontainers, such as a vial, an ampoule, a cartridge, or a syringe.Preferably, one or more of the filtration steps and the filling step areperformed under aseptic conditions in order to provide a sterilecontainer comprising a sterile composition.

The invention also provides a container comprising a compositioncomprising fulvestrant, a pharmaceutically acceptable alcohol,polysorbate 80, an antioxidant, and castor oil. In certain embodiments,the container is a vial, an ampoule, a cartridge, or a syringe. In someembodiments, the container, the composition, or both the container andthe composition are sterile.

In certain embodiments, the invention provides a pre-filled syringecontaining a composition of the invention described herein. In certainembodiments, a syringe according to the invention is a component of anautoinjector. Preferably, the container is sealed by way of a closure,such as a stopper, plunger, and/or tip-cap. The container and closurecan be made of glass, plastic, and/or rubber.

It has been surprisingly discovered that a composition comprisingfulvestrant, a pharmaceutically acceptable alcohol, polysorbate 80, anantioxidant, and castor oil may have increased stability over acomposition comprising fulvestrant, a pharmaceutically acceptablealcohol, a non-aqueous ester solvent, and castor oil, such as theFASLODEX™ (fulvestrant) injection product. The term “stability” as usedherein with respect to a composition is meant to encompass anycharacteristic of a composition which may be affected by storageconditions including, without limitation, total impurities, fulvestrantdegradation products, specific optical rotation, optical purity, watercontent, appearance, viscosity, sterility, and color and clarity.Methods for determining the stability of a composition of the inventionwith respect to a given parameter are well-known to those of skill inthe art. For example, fulvestrant degradation products and totalimpurities can be assessed by high-performance liquid chromatography(HPLC) or thin layer chromatography (TLC).

In some embodiments, when a composition of the invention is stored at2°-8° C., 25° C., or 40° C. for a period of 3 months, the amount oftotal impurities present in the composition is not more than 1%. Anysuitable method can be used to determine the amount of total impuritiespresent in the composition. Preferably, the amount of total impuritiesis calculated as the sum of the area under the peak of each impurity asa percentage of the total area under all peaks observed in an HPLCchromatogram. In other embodiments, when a composition of the inventionis stored at 2°-8° C., 25° C., or 40° C. for a period of 3 months, theamount of total impurities present in the composition is not more than0.9%, e.g., not more than 0.8%, not more than 0.7%, not more than 0.6%,not more than 0.5%, not more than 0.4%, not more than 0.3%, not morethan 0.2%, or not more than 0.1%. In yet other embodiments, when acomposition of the invention is stored at 2°-8° C., 25° C., or 40° C.for a period of 3 months, the amount of total impurities present in thecomposition is 0.1%-1%, 0.1%-0.8%, 0.3%-0.7%, 0.4%-0.9%, 0.1%-0.5%, or0.2%-1%.

In certain embodiments, when a composition of the invention is stored atroom temperature for a period of 12 months, the amount of totalimpurities present in the composition is not more than 2.0%. In otherembodiments, when a composition of the invention is stored at roomtemperature for a period of 12 months, the amount of total impuritiespresent in the composition is not more than 1.8%, e.g., not more than1.6%, not more than 1.5%, not more than 1.4%, not more than 1.2%, notmore than 1.0%, not more than 0.8%, not more than 0.7%, or not more than0.6%. In yet other embodiments, when a composition of the invention isstored at room temperature for a period of 12 months, the amount oftotal impurities present in the composition is 0.6%-2.0%, 0.7%-1.6%,0.8%-1.8%, 1.0%-1.5%, 0.8%-1.2%, or 0.6%-1.4%.

Fulvestrant sulfone is an oxidative degradation product of fulvestrant.In some embodiments, when a composition of the invention is stored at2°-8° C., 25° C., or 40° C. for a period of 3 months, the amount offulvestrant sulfone present in the composition is not more than 0.5%.Any suitable method can be used to determine the amount of fulvestrantsulfone present in the composition. Preferably, the amount offulvestrant sulfone is calculated as the area under the fulvestrantsulfone peak as a percentage of the total area under all peaks observedin an HPLC chromatogram. In other embodiments, when a composition of theinvention is stored at 2°-8° C., 25° C., or 40° C. for a period of 3months, the amount of fulvestrant sulfone present in the composition isnot more than 0.45%, e.g., not more than 0.4%, not more than 0.35%, notmore than 0.3%, not more than 0.25%, not more than 0.2%, not more than0.15%, not more than 0.1%, not more than 0.09%, not more than 0.07%, ornot more than 0.05%. In yet other embodiments, when a composition of theinvention is stored at 2°-8° C., 25° C., or 40° C. for a period of 3months, the amount of fulvestrant sulfone present in the composition is0.1%-1%, 0.1%-0.8%, 0.3%-0.7%, 0.4%-0.9%, 0.1%-0.5%, or 0.2%-1%.

In some embodiments, when a composition of the invention is stored atroom temperature for a period of 12 months, the amount of fulvestrantsulfone present in the composition is not more than 1.0%. In otherembodiments, when a composition of the invention is stored at roomtemperature for a period of 12 months, the amount of fulvestrant sulfonepresent in the composition is not more than 0.9%, e.g., not more than0.8%, not more than 0.75%, not more than 0.7%, not more than 0.6%, notmore than 0.55%, not more than 0.5%, not more than 0.4%, not more than0.3%, or not more than 0.25%. In yet other embodiments, when acomposition of the invention is stored at room temperature for a periodof 12 months, the amount of fulvestrant sulfone present in thecomposition is 0.25%-1.0%, 0.25%-0.75%, 0.4%-0.8%, 0.3%-0.6%, 0.5%-1.0%,or 0.5%-0.9%.

The invention also provides a method of stabilizing a fulvestrantcomposition by forming a mixture comprising fulvestrant, apharmaceutically acceptable alcohol, polysorbate 80, an antioxidant, andcastor oil, thereby stabilizing the composition. The identity andamounts of fulvestrant, a pharmaceutically acceptable alcohol,polysorbate 80, an antioxidant, and castor oil present in the mixturecan be the same as the identity and amounts of these componentsdescribed herein with respect to a composition of the invention.Preferably, the mixture, and the composition thus formed, issubstantially free, or completely free, of a non-aqueous ester solvent.The composition formed by the method of stabilizing a fulvestrantcomposition can have the same stability characteristics as the stabilitycharacteristics described herein with respect to a composition of theinvention, particularly with regard to total impurities and fulvestrantsulfone.

The composition according to the invention is suitable foradministration to a subject to treat or prevent a disease or condition.Preferably, the disease or condition is a disease or condition of thebreast or of the female reproductive tract. The disease or condition canbe benign, or the disease or condition can be malignant.

In some embodiments, the invention provides a method of treating hormonereceptor positive metastatic breast cancer in a subject in need thereof.The method comprises administering a therapeutically effective amount ofa composition of the invention to the subject, thereby treating thehormone receptor positive metastatic breast cancer in the subject.Preferably, the composition is administered to the subject byintramuscular injection. The therapeutically effective amount of acomposition of the invention can be administered in a single injection,or divided into two or more injections.

The therapeutically effective amount of a composition of the inventioncan be determined empirically by one of ordinary skill in the art basedupon, for example, the concentration of fulvestrant in the composition,the identity and severity of the disease or condition to be treated, andsubject-specific considerations such as body weight or age. In someembodiments, the volume of the composition administered per injection is5 mL or less, e.g., 4.5 mL or less, 4 mL or less, 3.5 mL or less, 3 mLor less, 2.5 mL or less, or 2 mL or less. In other embodiments, thevolume of the composition administered per injection is 1 mL or more,e.g., 1.5 mL or more, 2 mL or more, 2.5 mL or more, 3 mL or more, 3.5 mLor more, or 4 mL or more. In yet other embodiments, the volume of thecomposition administered per injection is in a range bounded by any ofthe foregoing values. For example, the volume of the compositionadministered per injection can be 1.5 mL-3 mL, 2 mL-4 mL, 2.5 mL-4.5 mL,3 mL-5 mL, 3.5 mL-4.5 mL, or 4 mL-4.5 mL. In certain embodiments, thevolume of the composition administered per injection is about 5 mL.

A composition of the invention can be administered as a monotherapy, ora composition of the invention can be a component of a combinationtherapy comprising the administration of fulvestrant and one or moreadditional drugs. If a component of a combination therapy, a compositionof the invention can be administered prior to, substantially concurrentwith, or after the administration of the one or more additional drugs.

Other than in the operating examples, or where otherwise indicated, allnumbers expressing quantities of ingredients, reaction conditions, andso forth used in the specification and claims are to be understood asbeing modified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained by the present disclosure. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldbe construed in light of the number of significant digits and ordinaryrounding approaches.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the disclosure are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contain certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements.

The following examples are intended to illustrate the invention in anon-limiting manner.

Example 1

This example demonstrates the effect of polysorbate 80 on the solubilityof fulvestrant in an oil based liquid formulation.

U.S. Pat. No. 6,774,122 discloses that the solubility of fulvestrant incastor oil is 20 mg/mL, and that the solubility of fulvestrant in acastor oil vehicle containing 10% ethanol, 10% benzyl alcohol, and 15%benzyl benzoate is 65 mg/mL. To determine the effect of other compoundson the solubility of fulvestrant in a castor oil vehicle containing 10%ethanol and 10% benzyl alcohol, several liquid formulations wereprepared by mixing using standard techniques, as summarized in Table 1.Fulvestrant solubility in each formulation was determined by an HPLCassay.

TABLE 1 Component % w/v Ethanol 10 10 10 10 10 10 10 10 Benzyl alcohol10 10 10 10 10 10 10 10 Ethyl oleate 15 — — — — — — — Isopropylmyristate — 15 — — — — — — Isopropyl palmitate — — 15 — — — — —Polysorbate 80 — — — 0.2 0.16 0.1 0.09 0.05 Castor oil q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. Solubility (mg/ml)   66.8   63.9   67.6 95.090.0 82.5 82.1 76.5

The solubility of fulvestrant in the presence of the non-aqueous estersolvent ethyl oleate, isopropyl myristate, or isopropyl palmitate wassimilar to the solubility of fulvestrant in the presence of thenon-aqueous solvent, benzyl benzoate, as reported in U.S. Pat. No.6,774,122.

Remarkably, the presence of polysorbate 80 greatly increased thesolubility of fulvestrant in a castor oil based formulation, even in theabsence of any non-aqueous ester solvent.

The results of this example demonstrate that polysorbate 80 enhances thesolubility of fulvestrant in a castor oil based formulation to a greaterextent than non-aqueous ester solvents, such as benzyl benzoate, ethyloleate, isopropyl myristate, and isopropyl palmitate.

Example 2

This example demonstrates the effect of polysorbate 80 and anantioxidant on the stability of an oil based liquid formulationcontaining fulvestrant.

The FASLODEX™ (fulvestrant) injection product must be stored underrefrigeration at 2°-8° C. until the time of use. To determine the effectof polysorbate 80 and an antioxidant on the stability an oil basedliquid formulation containing fulvestrant, a reference formulationrepresenting the FASLODEX™ (fulvestrant) injection product (“RLD”) andseveral formulations according to the invention were prepared by mixingusing standard techniques, as summarized in Table 2.

TABLE 2 Benzyl Benzyl Polysorbate α- Castor Ethanol alcohol benzoate 80tocopherol Fulvestrant oil Formulation (% w/v) RLD 10 10 15 — — 5.0 q.s.A 10 10 — 0.12 0.06 7.5 q.s. B 15 10 — 0.12 0.06 10.0 q.s. C 10 10 —0.12 0.06 5.0 q.s. D 17 10 — 0.12 0.06 5.0 q.s.

Samples of the RLD and each of Formulations A-D were stored for 3 monthsat 25° C. At the end of the storage period, the amounts of sulfoneimpurity and total impurities were measured using an HPLC assay. Theresults of the storage stability testing are summarized in Table 3.

TABLE 3 Sulfone impurity Total impurities Formulation (% w/w) (% w/w)RLD 0.30 1.25 A 0.50 0.64 B 0.32 0.60 C 0.45 0.78 D 0.21 0.35

The amount of sulfone impurity following storage for 3 months at 25° C.was approximately the same for each of the RLD and Formulations A-D.However, the amount of total impurities was greatly reduced in each ofFormulations A-D as compared with the RLD.

To further examine the effect of an antioxidant on stability, severalformulations containing 5% fulvestrant, 10% ethanol, 10% benzyl alcohol,0.06% α-tocopherol and 0.12% polysorbate 80 in castor oil were preparedand supplemented with 0%, 2%, 4%, 8%, or 12% α-tocopherol. Samples ofeach formulation were stored for 3 months at 2-8° C., 25° C., or 40° C.At the end of the storage period, the amounts of sulfone impurity andtotal impurities were measured using an HPLC assay. The results of thestorage stability testing are summarized in Table 4.

TABLE 4 Supplemental α-tocopherol Sulfone impurity (% w/w) Totalimpurities (% w/w) (w/v) 2-8° C. 25° C. 40° C. 2-8° C. 25° C. 40° C. 0.00.09 0.17 0.29 0.4 0.5 0.7 2.0 0.13 0.16 0.37 0.4 0.5 0.7 4.0 0.10 0.130.16 0.5 0.4 0.5 8.0 0.13 0.16 0.19 0.7 0.6 0.6 12.0 0.10 0.19 0.25 0.80.8 0.7

The amounts of sulfone impurity and total impurities were similarfollowing storage for 3 months at 2-8° C., 25° C., or 40° C.irrespective of the amount of α-tocopherol added to the base formulationwhich contained 0.06% α-tocopherol.

The results of this example demonstrate that the combination ofpolysorbate 80 and an antioxidant increases the stability of fulvestrantin oil based liquid formulations.

Example 3

This example demonstrates the pharmacokinetics of fulvestrant followingadministration of an oil based liquid formulation containing benzylbenzoate or a combination of polysorbate 80 and an antioxidant.

A dose of 33.33 mg/kg of the commercial FASLODEX™ (fulvestrant)injection product or one of Formulations A-D as described in Example 2was delivered by injection to the buttocks of female rabbits (n=6 pergroup). The dose volume was divided equally on two sites of injectionper rabbit. Blood samples were collected prior to dosing, and at 2, 4,6, 8, 12, 16, 24, 48, 72, 120, 168, 336, 504, and 672 hours afterdosing. The concentration of fulvestrant in the plasma was determinedusing an HPLC assay.

The time course of fulvestrant plasma concentration was similar inrabbits dosed with the FASLODEX™ product or any one of Formulations A-D(FIG. 1). The mean T_(max) and C_(max), and the mean AUC relative to theFASLODEX™ product observed in this study are summarized in Table 5.

TABLE 5 T_(max) C_(max) Relative AUC_(0-t) Relative AUC_(inf) Treatment(hr) (ng/mL) (ng*hr/mL) (ng*hr/mL) FASLODEX ™ 84 21.7 100 100 A 96 17.692.3 111 B 60 17.8 81.2 92.1 C 120 18.7 95.9 97.2 D 120 20.0 93.9 102

A one-way ANOVA of log-transformed data of the calculated C_(max),AUC_(0-t), and AUC_(inf) values yielded p-values of 0.1938, 0.1431, and0.1071, respectively. Thus, there was no significant difference in theC_(max), AUC_(0-t), and AUC_(inf) achieved following administration torabbits of the FASLODEX™ product as compared to any one of FormulationsA-D.

The results of this example demonstrate that oil based liquidformulations containing fulvestrant, polysorbate 80, and an antioxidantprovide similar pharmacokinetics as an oil based liquid formulationcontaining fulvestrant and the non-aqueous ester solvent, benzylbenzoate.

Example 4

This example demonstrates a method for making a composition comprisingfulvestrant, a pharmaceutically acceptable alcohol, polysorbate 80, anantioxidant, and castor oil.

An exemplary composition according to the invention is described inTable 6.

TABLE 6 Component Amount Fulvestrant 50 mg/mL Ethyl alcohol, 190 proof,NF  10% Benzyl alcohol, USP  10% Polysorbate 80 0.12% α-tocopherol 0.06%Castor oil (super refined) q.s.

The composition is prepared according to the following generalprocedure. Benzyl alcohol is added into a stainless steel tank held atroom temperature. Ethyl alcohol is added into the tank, and thecomposition is mixed for not less than 5 minutes. Fulvestrant is addedinto the tank, and the composition is mixed for not less than 30 minutesuntil the fulvestrant is dissolved. Polysorbate 80 and α-tocopherol areadded into the tank, and the composition is mixed for not less than 5minutes. Super refined castor oil is added to the tank to approximately70% of the final volume. The tank is pressurized with nitrogen, and thecomposition is mixed for not less than 30 minutes. Super refined castoroil is added to the tank until the final volume is obtained. The tank ispressurized with nitrogen, and the composition is mixed for not lessthan 60 minutes, at which point the composition should be clear toslightly hazy. The composition is filtered through a pre-filter having apore diameter of 0.45 μm into a suitable vessel.

The composition is then filtered through a final filter having a porediameter of 0.2 μm into a pressure tank fitted with a filling needleunder aseptic conditions. The composition is dispensed into a suitablecontainer, and the filled container is sealed.

This example provides a suitable method to prepare a compositionaccording to the invention.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and “at least one” andsimilar referents in the context of describing the invention (especiallyin the context of the following claims) are to be construed to coverboth the singular and the plural, unless otherwise indicated herein orclearly contradicted by context. The use of the term “at least one”followed by a list of one or more items (for example, “at least one of Aand B”) is to be construed to mean one item selected from the listeditems (A or B) or any combination of two or more of the listed items (Aand B), unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

What is claimed is:
 1. A composition comprising fulvestrant and apharmaceutically acceptable vehicle, wherein the composition issubstantially free of a non-aqueous ester solvent and comprises not morethan 2% total impurities.
 2. The composition of claim 1, wherein thecomposition is completely free of a non-aqueous ester solvent.
 3. Thecomposition of claim 1, wherein the composition comprises at least oneof a pharmaceutically acceptable alcohol, a nonionic surfactant, and anantioxidant.
 4. The composition of claim 3, wherein the compositioncomprises at least two of a pharmaceutically acceptable alcohol, anonionic surfactant, and an antioxidant.
 5. The composition of claim 2,wherein the composition comprises a pharmaceutically acceptable alcohol,a nonionic surfactant, and an antioxidant.
 6. The composition of claim1, wherein the vehicle is an oleaginous vehicle.
 7. The composition ofclaim 1, wherein the total impurities are determined following storageof the composition at room temperature for a period of 12 months.
 8. Thecomposition of claim 1, comprising not more than 1% total impurities. 9.The composition of claim 8, wherein the total impurities are determinedfollowing storage of the composition at 2-40° C. for a period of 3months.
 10. The composition of claim 9, wherein the total impurities aredetermined following storage of the composition at 25° C.
 11. Acontainer comprising 2.5 mL-5 mL of the composition of claim
 1. 12. Thecontainer of claim 11, wherein the container is a vial, an ampoule, acartridge, or a syringe.
 13. A method of treating hormone receptorpositive metastatic breast cancer in a subject in need thereof, themethod comprising administering a therapeutically effective amount ofthe composition of claim 1 to the subject, thereby treating the hormonereceptor positive metastatic breast cancer in the subject.
 14. Acomposition comprising 4% w/v or more fulvestrant, a nonionicsurfactant, and not more than 2% total impurities.
 15. The compositionof claim 14, wherein the composition is substantially free of anon-aqueous ester solvent.
 16. The composition of claim 14, wherein thecomposition comprises an oleaginous vehicle.
 17. The composition ofclaim 14, wherein the nonionic surfactant is polysorbate
 80. 18. Thecomposition of claim 14, wherein the composition comprises apharmaceutically acceptable alcohol and/or an antioxidant.
 19. Thecomposition of claim 14, wherein the total impurities are determinedfollowing storage of the composition at room temperature for a period of12 months.
 20. A container comprising 2.5 mL-5 mL of the composition ofclaim 14.